Screening drug target combinations in disease-related molecular networks

For treating a complex disease such as cancer, some effective means are needed to control biological networks that underlies the disease. The one-target one-drug paradigm has been the dominating drug discovery approach in the past decades. Compared to single target-based drugs, combination drug targets may overcome many limitations of single drug target and achieve a more effective and safer control of the disease. Most of existing combination drug targets are developed based on clinical experience or text-and-trial strategy, which cannot provide theoretical guidelines for designing and screening effective drug combinations. Therefore, systematic identification of multiple drug targets and optimal intervention strategy needs to be developed.

We developed a strategy to screen the synergistic combinations of two drug targets in disease networks based on the classification of single drug targets. The method tried to identify the sensitivity of single intervention and then the combination of multiple interventions that can restore the disease network to a desired normal state. In our strategy of screening drug target combinations, we first classified all drug targets into sensitive and insensitive single drug targets. Then, we identified the synergistic and antagonistic of drug target combinations, including the combinations of sensitive drug targets, the combinations of insensitive drug target and the combination of sensitive and insensitive targets. Finally, we applied our strategy to Arachidonic Acid (AA) metabolic network and found 18 pairs of synergistic drug target combinations, five of which have been proven to be viable by biological or medical experiments.

Different from traditional methods for judging drug synergy and antagonism, we propose the framework of how to enhance the efficiency by perturbing two sensitive targets in a combinatorial way, how to decrease the drug dose and therefore its side effect and cost by perturbing combinatorially a main sensitive target and an auxiliary insensitive target, and how to perturb two insensitive targets to realize the transition from a disease state to a healthy one which cannot be realized by perturbing each insensitive target alone. Although the idea is mainly applied to an AA metabolic network, the strategy holds for more general molecular networks such as combinatorial regulation in gene regulatory networks.